Altered transition metal homeostasis in Niemann-Pick disease, type C1.

Abstract

The loss of NPC1 protein function is the predominant cause of Niemann-Pick type C1 disease (NP-C1), a systemic and neurodegenerative disorder characterized by late-endosomal/lysosomal accumulation of cholesterol and other lipids. Limited evidence from post-mortem human tissues, an Npc1(-/-) mouse model, and cell culture studies also suggest failure of metal homeostasis in NP-C1. To investigate these findings, we performed a comprehensive transition metal analysis of cerebrospinal fluid (CSF), plasma and tissue samples from human NP-C1 patients and an Npc1(-/-) mouse model. NPC1 deficiency in the Npc1(-/-) mouse model resulted in a perturbation of transition metal homeostasis in the plasma and key organs (brain, liver, spleen, heart, lungs, and kidneys). Analysis of human patient CSF, plasma and post-mortem brain tissues also indicated disrupted metal homeostasis. There was a disparity in the direction of metal changes between the human and the Npc1(-/-) mouse samples, which may reflect species-specific metal metabolism. Nevertheless, common to both species is brain zinc accumulation. Furthermore, treatment with the glucosylceramide synthase inhibitor miglustat, the only drug shown in a controlled clinical trial to have some efficacy for NP-C1, did not correct the alterations in CSF and plasma transition metal and ceruloplasmin (CP) metabolism in NP-C1 patients. These findings highlight the importance of NPC1 function in metal homeostasis, and indicate that metal-targeting therapy may be of value as a treatment for NP-C.

• Authors: Ya Hui Hung, Noel G Faux, David W Killilea, Nicole Yanjanin, Sally Firnkes, Irene Volitakis, George Ganio, Mark Walterfang, Caroline Hastings, Forbes D Porter, Daniel S Ory, Ashley I Bush
• Journal: Metallomics : integrated biometal science (Metallomics) Vol. 6 Issue 3 Pg. 542-53 (Mar 2014) ISSN: 1756-591X [Electronic] England
• PMID: 24343124 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Intracellular Signaling Peptides and Proteins
• Metals
• Niemann-Pick C1 Protein
• Npc1 protein, mouse
• Proteins
• Transition Elements
• 1-Deoxynojirimycin
• miglustat
• Ceruloplasmin

Topics

• 1-Deoxynojirimycin (analogs & derivatives, therapeutic use)
• Animals
• Brain (metabolism, pathology)
• Ceruloplasmin (antagonists & inhibitors, metabolism)
• Enzyme Inhibitors (therapeutic use)
• Female
• Gene Deletion
• Homeostasis
• Humans
• Intracellular Signaling Peptides and Proteins
• Male
• Metals (blood, cerebrospinal fluid, metabolism)
• Mice
• Mice, Inbred BALB C
• Niemann-Pick C1 Protein
• Niemann-Pick Disease, Type C (blood, cerebrospinal fluid, drug therapy, metabolism)
• Proteins (genetics)
• Transition Elements (blood, cerebrospinal fluid, metabolism)